TW201201840A - Antibodies specifically binding to human TSLPR and methods of use - Google Patents

Abstract

An antibody specifically binding to human thymic stromal lymphopoietin receptor (TSLPR), characterized in comprising as heavy chain variable domain CDR regions a CDR1 region of SEQ ID NO: 2 or 17, a CDR2 region of SEQ ID NO: 3 or 10, and CDR3 region of SEQ ID NO: 4, and as light chain variable domain CDR regions a CDR1 region of SEQ ID NO: 6 or 12, a CDR2 region of SEQ ID NO: 7, 13 or 15, and a CDR3 region of SEQ ID NO: 8 is useful for the treatment of immunological diseases.

Description

201201840 VI. Description of the Invention: [Technical Field] The present invention relates to an antibody (TSLPR antibody) which specifically binds to human TSLPR, a method for producing the same, a pharmaceutical composition containing the same, and a use thereof. [Prior Art] The thymic stromal lymphopoietin receptor (TSLPR, TSLP receptor, CLRF2, SwissProt Q9HC73) is a type I cytokine receptor subunit closely related to the common cytokine γ chain (γ0). The TSLP system initiates and transports an allergic immune response to interleukin (IL)-7-like cytokines. TSLP is mainly produced by epithelial cells and activated mast cells and stimulates bone marrow dendritic cells (mDC), which exhibit heterodimers composed of interleukin 7 (IL-7) alpha chain and TSLP receptors. TSLP-activated mDC promotes the differentiation of naive CD4+ T cells into a Th2 phenotype and promotes CD4+Th2 memory cell expansion.

The human TSLP receptor is referred to as "generating cytokine receptor gamma-like" in WO 99/47538 (US 6,844,170, US 6,861,227, US 6,982,320) and WO 2001/12672. The human TSLP receptor is also in Pandey, A. et al, Nature Immunol. 1 (2000) 59-64, Soumelis, V. et al, Nature Immunol. 3 (2002) 673-680, Soumelis, V. et al., Springer Sem. Immunopath. 25 (2004) 325-333, WO

2002/068646 (US 6,890,734 'US 7,071,308) 'WO 2003/ 065985, WO 2002/00723, (US 6,955,895) 'WO 2002/00724, WO 99/47538, (US 6,844,170, US 6,861,227, US

I 6 > 82, 320), US 2005/249712 and WO 2006/023791 are mentioned. 156874.doc 201201840 Antibodies to TSLP receptors are also mentioned in WO 2007/112146 and WO 2009/100324. SUMMARY OF THE INVENTION The present invention comprises an antibody that specifically binds to TSLPR, characterized by comprising a CDR1 region of SEQ ID NO: 2, a CDR2 region of SEQ ID NO: 3, and SEQ ID as a heavy chain variable domain CDR region a CDR3 region of NO:4, and a CDR1 region of SEQ ID NO:6, a CDR2 region of SEQ ID NO:7, and a CDR3 region of SEQ ID NO:8 as a light chain variable domain CDR region, or humanization thereof Variants The invention comprises an antibody that specifically binds to TSLPR, characterized in that the heavy chain variable domain comprises SEQ ID ΝΟ:1 and the light chain variable domain comprises SEQ ID NO:5. The invention encompasses antibodies that specifically bind to TSLPR and are characterized by chimeric or humanized variants thereof. Preferably, the humanized variant is characterized by comprising a CDR1 region of SEQ ID NO: 2 or 17 as a heavy chain variable domain CDR region, a CDR2 region of SEQ ID NO: 3 or 10, and SEQ ID NO: 4 The CDR3 region' and the CDR1 region of SEQ ID NO: 6 or 12, the CDR2 region of SEQ ID NO: 7, 13, or 15 and the CDR3 region of SEQ Π) NO: 8 as the light chain variable domain CDR region. The humanized antibody of the present invention is preferably characterized by comprising a) a CDR1 region of SEQ ID NO: 2, a CDR2 region of SEQ ID NO: 10, and a SEQ ID NO: 4 as a heavy chain variable domain CDR region

CDR3 region, and SEq ID as the CDR region of the light chain variable domain

The CDR1 region of NO: 12, the CDR2 region of SEQ ID NO: 13, and the CDR3 region of SEQ 156874.doc 201201840 ID NO: 8, b) the CDR1 region of SEQ ID NO: 2 as the heavy chain variable domain CDR region a CDR2 region of SEQ ID NO: 1 and a CDR3 region of SEQ ID N: 4, and a CDR1 region of seq1 NO: 12, a CDR2 region of SEQ ID NO: 15 as a CDR region of a light chain variable domain, And the CDR3 area of SEq 'ID NO:8,

I: C) as the heavy chain variable domain CDR region, the CDR1 region of SEQ ID NO: 17, the CDR2 region of SEQ ID NO: 1 and the CDR3 region of SEQ ID N: 4, and is variable as a light chain The CDR1 region of SEq Hill NO:12, the CDR2 region of SEQ ID NO:15, and the CDR3 region of SEq ID NO:8, or d) as the heavy chain variable domain CDR region of SEQ ID NO: a CDR1 region of 2, a CDR2 region of SEQ ID NO: 1 and a CDR3 region of SEQ ID N: 4, and a CDR1 region of SEQ id NO: 12 as a CDR region of a light bond variable domain, SEQ ID NO: The CDR2 region of 7 and the CDR3 region of SEq ID NO:8.

I. The humanized antibody of the present invention is preferably characterized by comprising

I a) The heavy chain variable domain comprises SEq id NO:9 and the light chain variable domain • comprises SEQ ID NO. 11, - b) the heavy chain variable domain comprises SEQ ID NO: 9 and the light chain is variable The domain comprises SEQ ID NO: 14, : c) the heavy chain variable domain comprises SEq ID NO: 16 and the light chain variable domain comprises SEQ ID NO: 18, or d) the heavy chain variable domain comprises SEQ ID NO: 9 and the light chain variable domain 156874.doc 201201840 comprises SEQ ID NO: 19 » preferably, an anti-systemic human or human antibody. Preferably, the antibody of the present invention belongs to the human κ isotype. The antibody of the present invention preferably comprises an Fc portion derived from human origin. Preferably, the antibody of the present invention belongs to the human IgG 1 or IgG4 isotype. Preferably, the antibody belongs to the human IgG4 (S228P, L235E) class. Preferably, the antibody of the invention is characterized in that the heavy chain variable domain is a CDR-grafted IgG4 (S228P, L235E) subtype of the heavy chain variable domain and the CDR of the chain variable domain is a light chain variable domain Transplantation of the κ isoform. An example of an IgG4 (S228P, L235E) invariant chain is provided in the sequence listing below (SEQ ID NO: 22). IgG4 (S228P, L235E) means that dextran 228 in IgG4 is substituted with valine and substituted with 235 to glutamic acid. As with IgGl (LALA)-like, IgGl (L234A/L235A) should be understood as such. Preferably, the antibody of the present invention is characterized in that the antibody does not bind to complement factor Clq, which means that the maximum binding (Bmax) of the antibody to Clq at a concentration of 10 pg/ml and a molecular weight of 150.000 in the ELISA assay is determined by TSLP- The variable region of 012 and the human light chain kappa region SEQ ID NO: 23 and the human heavy chain IgG1 region SEQ ID NO: 20 chimeric antibody (Chimeric Mab TSLPR-012) have a Bmax of 30% or less, Good 20% or lower. Preferably, the antibody of the present invention is characterized in that the antibody does not bind to the Fey receptor on NK cells, which means that the maximum binding (Bmax) of the antibody to NK cells at a concentration of 20 pg/ml in the assay is the antibody Chimeric Mab. TSLPR-012 has a Bmax of 20% or less, preferably 10% or less. The antibody of the invention is characterized in that it does not bind to FcyRI. This means that the antibody is characterized by an analysis of the lack of FqRIIA and FcyllB in the range of 0.078-10 pg/ml for the binding of recombinant FcyRI2 B•cell lymphoma cells in the range of 0.078-10 pg/ml. The EC50 value of the antibody at the time of measurement is 5 times or more, preferably 7 times or more, for example 8 times or more, of the EC50 value of Chimeric Mab TSLPR-012. Preferably, the antibody of the present invention is characterized in that it comprises at least one IgG4 antibody or IgGi antibody having an amino acid mutation (preferably located in the human Fc portion) which allows it to not bind to the complement factor Clq and/or Binding to the human Fey receptor on NK cells. The antibody of the present invention is preferably characterized in that it belongs to the human subclass IgG4. In a further preferred embodiment of the invention, the antibody is characterized by belonging to any IgG class, preferably IgG1 or IgG4, which is at E233, L234, L235, G236, D270, N297, E318, K320, K322, A327, A330, P331 and/or P329 (according to the EU index number) contain at least one beam change. Especially preferred are IgG1 mutations PVA236, L234A/L235A and/or

I GLPSS331, and IgG4 mutation L235E. More preferably, the IgG4 subclass antibody contains the mutation S228P or the mutations S228P and L235E (Angal, S. et al. - Mol. Irnmunol 30 (1993) 105-108). Therefore, the antibody of the present invention preferably contains an antibody of human subclass IgG4 from one or more of PVA236, GLPSS331, and/or has a mutation.

I L234A/L23 5A (LALA mutation) (subject to the EU index number) of the human IgG1 subclass. Preferably, the antibody of the invention is characterized by binding to TSLPR, belonging to the IgG1 class, preferably comprising SEQ ID NO: 20 as the gamma heavy chain, optionally comprising the mutation L234A/L235A. Preferably, the antibody of the invention is characterized by belonging to the IgG4 class, optionally 156874.doc 201201840 comprising the S228P and/or L235E mutations. Preferably, the antibody color of the present invention comprises, as desired, the heavy chain constant region of SEQ ID NO: 21 of S228P and/or L235E and more preferably the light chain constant region of SEQ ID NO: 23. Preferably, the constant region of the antibody of the invention has SEQ ID NOS: 21 and 22. The antibody of the present invention is preferably characterized in that it does not elicit complement dependent cytotoxicity (CDC). The antibody of the present invention is preferably characterized in that it does not elicit antibody-dependent cellular cytotoxicity (ADCC). Thus, the invention encompasses an anti-TSLPR antibody or a single heavy or light chain, characterized by a CDR, a variable region, an intact amino acid sequence or a hybridoma, and which does not comprise an Fc portion or comprises any type of Fc portion, Preferred human IgGl Fc or human IgG4 Fc, unmodified from human sources or modified by the above mutations. Accordingly, the present invention also encompasses antibodies (preferably monoclonal antibodies) which are characterized in that they specifically bind to TSLPR, contain an Fc portion derived from human origin, and do not bind to human complement factor Clq and/or NK cells. Human Fey receptor, human IgG1 or human IgG4 belonging to human IgG4 type or both modified by the above mutation. The antibody of the present invention specifically binds TSLPR-transfected BA/F3 cells with at least 1 (Γ9 M·1, preferably 10-9 M·1 to 10_12 M·1 EC50 value (ACC 300, DSMZ, http://www Human TSLPR (FACS analysis) on .dsmz.de). The antibody of the present invention inhibits proliferation of BA/F3-TSLPR/IL7Rct by a ratio of 40/1111 or lower (:5() value (]^\¥150.000). In one embodiment, an antibody of the invention inhibits dendritic cell (DC) activation and cytokine/chemokine secretion with an IC50 156874.doc 201201840 value of 6.0 nM or less. In one embodiment, the invention is The antibody inhibits TARC dendritic cell (DC) activation and cytokine/chemokine secretion at an IC5 threshold of 3.0 nM or lower.

In one embodiment, the antibody of the invention is measured by the ic50 value of 30 nM or lower as the Th2 polarization produced by the IL-13 cytokine. In one embodiment, the antibody of the present invention is measured by the inhibition of IC5() of 2.0 nM or less as the Th2 polarization produced by the IL-5 cytokine. In one embodiment, an antibody of the invention blocks cytokine production in mast cells when stimulated with TSLP and IL-33 or TSLP and TNFa/IL-1 beta. In one embodiment, the antibody of the invention, when stimulated with TSLP and IL_33, blocks IL_13 cytokine production in mast cells with an IC5 value of 〇 9 nM or less. In one embodiment, the antibody of the invention, when stimulated with TSLp and IL-33, blocks the production of _5 cytokines in mast cells, 1 (: 5 〇 value is 0·04 nM or lower "in one In one embodiment, the antibody of the invention, when stimulated by 硐TSLP and IL-33, blocks gmcSF cytokine production in the mast cells with an ICso value of 〇.〇8 nM or lower. In one embodiment, the invention Antibodies that block IL-13 cytokine production in mast cells when stimulated with TSLP and IL-ip/TNFa, 1 (:5〇 value is n16 nM or lower. In one embodiment, the antibody of the invention Stimulation with TSLp & IL1p/TNFa blocks 乩5 cytokine production in mast cells with an IC5 〇 value of 0.13 nM or lower. In one embodiment, the antibodies of the invention are in TSLp and IL-ip /TNFa stimulation blocks gmcsf cytokine production in mast cells with an IC50 value of 0.26 nM or lower. Preferably, the antibody of the invention is characterized by the above amino acid sequence or the amino group 156S74.idoc 201201840 acid sequence fragment And the nature of the invention. The invention further comprises a nucleic acid encoding an antibody of the invention. The present invention is a nucleic acid encoding a heavy chain and a light chain of an antibody of the present invention. The present invention further comprises an expression vector comprising the nucleic acid of the present invention to express an antibody that specifically binds to TSLPR in a prokaryotic or eukaryotic host cell. Further comprising a prokaryotic or eukaryotic host cell comprising a vector of the invention. The invention further comprises a method of producing a recombinant antibody of the invention, characterized in that the nucleic acid of the invention is expressed in a prokaryotic or eukaryotic host cell and from the cell or cell culture The supernatant recovers the antibody. The antibodies of the invention are characterized in that the constant bond has a human source. Such chain is well known in the art and is, for example, by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition , Public Health Service, National Institutes of Health, Bethesda, MD (1991). As mentioned above, a useful human light chain constant region comprising the amino acid sequence is the κ-light bond constant region of SEQ ID NO: 23 and Useful human heavy chain constant regions comprise SEQ ID NO: 20, 21 or 22. The invention further comprises the feature comprising the invention The present invention further comprises a method of producing a pharmaceutical composition comprising an antibody of the present invention. The present invention further comprises a method of producing an agent for treating a disease, characterized by comprising an antibody which specifically binds to the human TSLPR of the present invention The invention further encompasses the use of an antibody of the invention for the manufacture of a pharmaceutical composition. The invention further encompasses the use of the antibodies of the invention for the manufacture of a medicament. The invention further encompasses the use of an antibody of the invention for the treatment of a disease. The invention further encompasses the use of an antibody of the invention, wherein the disease is 156874.doc • 10-201201840 disease. The invention further comprises an antibody of the invention for use in the treatment of a disease beta. The invention further comprises an antibody of the invention, wherein the disease is an immune disease. The invention further comprises a method of treating a patient suffering from a disease, characterized in that the antibody of the invention is administered to the patient. The invention further comprises a method of treatment according to the invention' characterized in that the disease is an immune disease. The invention encompasses a method of treating a patient in need of therapy, characterized in that a therapeutically effective amount of an antibody of the invention is administered to the patient. The disease to be treated is especially asthma, atopic dermatitis or rheumatoid arthritis and is characterized in particular by the activation of TSLPR activation. [Embodiment] For the purposes of this document, the "receptor human framework" comprises a light chain variable domain (vl) framework or a heavy-bond variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework. The framework of the amino acid sequence is as defined below. A human framework derived from a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or it may contain amino acid sequence changes. In some embodiments, the amount of amino acid change is greater than 1, 9, or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 & more J 3 Or smaller, or 2 or smaller. In some embodiments, the sequence plaque ντ A # ^ sequence of the acceptor human framework is identical to the VL human immunoglobulin framework sequence or the human ~ framed sequence. "Affinity" means the non-covalent interaction between a single-binding site of a molecule (eg, an antibody) and a "mouth partner (eg, an antigen), unless otherwise stated, otherwise used herein as "binding affinity; : Intensity. Combining 斟占昌 with '.Affinity' refers to the intrinsic knot reflecting the 1:1 interaction between 1 such as 'antibody and antigen' 156874.doc •11· 201201840 Affinity. The affinity of the molecule X for its partner gamma is generally represented by the dissociation constant (Kd) "Affinity can be measured by common methods known in the art, including those described herein, "Specific Interpretation for Measuring Binding Affinity" And example embodiments are set forth below. The term "antibody" encompasses various forms of antibody structures including, but not limited to, whole antibodies and antibody fragments. The antibody of the present invention is preferably a human antibody, a humanized antibody, a chimeric antibody or a further genetically modified antibody, as long as the characteristics of the present invention are maintained. The "antibody fragment" comprises a part of a full length antibody, preferably a variable domain thereof. , or at least its antigen binding site. Examples of antibody fragments include diabody, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments. scFv antibodies are described, for example, in Huston, J.S., Methods in Enzymol. 203 (1991) 46-88. In addition, the antibody fragment comprises a single-chain polypeptide having the characteristics that the VH domain binds to TSLPR, that is, can be assembled into a functional antigen-binding site together with the VL domain; or has the feature that the VL domain binds to TSLPR' The vH domains are assembled together into a functional antigen binding site and thereby provide the properties of the antibodies of the invention. The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of an antibody molecule having a single amino acid composition. The "antigen-binding portion of an antibody" as used herein refers to an amino acid residue responsible for binding an antigen to an antibody. The antigen-binding portion of the antibody comprises an amino acid residue of a "complementarity determining region" or a "CDR". base. The "framework" or "FR" regions are the variable domain regions other than the hypervariable region residues defined herein. Thus, the light and heavy chain variable domains of an antibody comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 from the N-terminus to the c-terminus 156874.doc 201201840 and FR4 » specifically, the CDR3 line of the heavy chain The region that has the greatest antigen binding and defines the properties of the antibody. The CDR and FR regions are based on Kabat et al. (Sequences of Proteins of Immunological Interest > 5th edition,

The definition of the standard of Public Health Service, National Institutes of Health, Bethesda, MD. (1991) and/or their residues from the "hypervariable loop" is determined. The term "amino acid" as used in this application denotes a naturally occurring carboxyl group alpha gamma acid group which comprises alanine (three letter code: ala, single letter code: A), arginine (arg, R), aspartic Indole (asn, N), aspartic acid (isp, D), cysteine (cys, c), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, kappa), methionine (met, Μ), seeking alanine (phe, F), valine (pr〇, ρ), serine (ser, s), threonine (thr, T), tryptophan (trp, W), cheese Amine acid (tyr, γ) and proline (val, V). The antibody of the present invention additionally includes such variants (variant antibodies) having a "conservative sequence modification", such antibodies having nucleotide and amino acid sequence modifications which do not affect or alter the above-described properties of the antibody of the present invention. . Modifications can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR mediation. Conservative seric acid substitutions include the replacement of an amino acid residue with a similar side bond. Anthraquinones having an amino acid residue similar to a side chain have been defined in the art to include amino acids having an indentation side bond (eg, 'isamino acid, arginine, histidine), Acidic side chain amino acid (4) such as aspartic acid, face acid # has an amine group without electrode side bonds 156874.doc 201201840 acid (such as 'glycine, aspartame, face amidoxime, Amine acid, sulphate, tyrosine, cysteine, tryptophan), amino acids with non-polar side chains (eg 'alanine, valine, leucine, isoleucine, Amidinoic acid, phenylalanine, methionine, an amino acid having a β-branched side chain (for example, sulphate, valine, isoleucine) and an amino acid having an aromatic side chain ( For example, 'tyramine, phenylalanine, tryptophan, histidine). Thus, the predicted non-essential amino acid residues in the human anti-TSLPR antibody may preferably be replaced by another amino acid residue from the same side chain family. Thus, the "variant" anti-TSLPR anti-system herein means that the amino acid sequence differs from the "parental" anti-TSLPR antibody amino acid sequence by up to 10 in one or more of the variable regions of the parent antibody. Preferably, from about 2 to about 5 added, deleted and/or substituted molecules. Amino acid substitution can be carried out by mutagenesis based on molecular modeling 'as by Riechmann, L. et al, Nature 332 (1988) 323-327 and Queen, C. et al. 'Proc. Natl. Acad. Sci. USA 86 (1989) 10029-10033. An "enemy" anti-system refers to an antibody from which a part or combination of heavy bonds and/or light bonds is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. Antibody "category" refers to the type of constant region owned by a strange domain or a double bond. There are five broad classes of antibodies: IgA, lgD, IgE, IgG, and IgM' and several of these classes can be further divided into subclasses (isotypes), for example, IgG, IgG2, IgG3, IgG4, IgA!, and IgA2. The heavy-chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ 分别 156874.doc -14- 201201840

I

"I 1 effector function" refers to the biological activity of the Fc region attributed to the antibody, which may vary depending on the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding 'antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis' cell surface receptors (eg, B cell receptors) Under the body; and B cells live.

I. An "effective amount" of a medicament (e.g., a 'pharmaceutical formulation) means an amount effective to achieve a desired therapeutic or prophylactic result at a desired dose over a desired period of time. The term "Fc region" is used herein to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a definitive region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226, or from Pr〇230 to the carboxy terminus of the heavy chain. However, the C-terminal amide acid (Lys447) of the Fc region may or may not be present. Unless otherwise indicated herein, the aminoguanidine residues in the Fc region or constant region are numbered according to the EU numbering system (also known as the EU index), such as

I K, abat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, (1991). Thus, the expression "amine's acid residue position is numbered according to Kabat" refers to the EU numbering system, also known as the EU index, as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, N To the Catholic Institutes of Health, Bethesda, MD, (1991): The terms "host cell", "host cell line" and "host cell culture 156874.doc 201201840" are used interchangeably and refer to cells into which exogenous nucleic acids are introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells" which include primary transformed cells and progeny derived therefrom (independent of the number of passages). The nucleic acid content of the progeny and parental cells may not be exactly the same, but may contain mutations. Described herein are mutant progeny that have been screened or selected for use in the original transformed cells with the same function or biological activity. The "Human Common Framework" represents the framework for the most prevalent amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. Usually, the sequence subgroup is like Kabat et al., Sequences 〇f

Proteins of Immunological interest, 5th edition, Public Heahh Service, National Institutes of Health, Public Publication 91_3242,

Bethesda MD (1991), No.! To the subgroup of the three volumes. In one embodiment, for VL, the subgroup is a subgroup <1 as described by Kabat et al. (see above). In one embodiment, for VH, the subgroup is a subgroup of III as described by Kabat et al. (see above). A "humanized" anti-system refers to a chimeric antibody comprising an amino acid residue from a non-human CDR and an amino acid residue from a human FR. In certain embodiments, a 'humanized antibody comprises substantially all of at least one, and typically all or substantially all of the two variable structures H correspond to the non-human antibodies, and all or substantially All FRs correspond to their FRs of human antibodies. The humanized antibody may optionally comprise at least a portion of the antibody-derived region derived from the human antibody. A "humanized form" or "humanized variant" or "humanized antibody" (eg, a non-human antibody) of an antibody refers to an antibody that has been subjected to humanization by 156874.doc 201201840. In one embodiment, one to all six CDRs of an antibody derived from a non-human species (e.g., hamster) are grafted into the framework regions of a human antibody to produce a "humanized antibody." For example, see

Riechmann, L. et al., Nature 332 (1988) 323-327; and Neuberger, M.S. et al., Nature 314 (1985) 268-270. in a

In the case of greed, "humanized variant of an antibody of the invention" (which has a non-human source (eg, hamster)) refers to an antibody based on a non-human antibody sequence, by standard techniques (including CDR grafting) and subsequently as needed Mutagenic framework area and cdR

Certain amino acids of I t to humanize VH and VL β. In one embodiment, one or five amino acids (eg, up to three) and/or CDRs in the framework regions may be modified by other mutations. One to three amino acids (for example, at most two). For example, mutagenesis can be based on molecular modeling, such as Riechmann, L et al.

Nature 332 (1988) 323-327 and Queen, C. et al., Proc. Natl. Acad. Sci. USA 86 (1989) 10029-10033 or others. can

If by (for example) sequence or homology analysis, by selecting a human frame (fixed frame

I_method; homology matching or best fit), by using consensus sequences, by selecting FRs from several different germlines, or by replacing the three-dimensional surface with the most common residues found in human antibodies Human sequences or based on stereo-optimized 4-mesh interactions determine the location suitable for such mutations. In one embodiment, the humanized variant is chimeric to a human constant region. : "consistency or homology" relative to a sequence is defined herein as an amine in the candidate sequence that is identical to the parent sequence in the car, sequence, and introduction of a gap (if necessary) to achieve a maximum percent sequence identity. The percentage of base acid residues. N-terminal, C-terminal or internal extension, deletion or insertion in the antibody sequence 156874jdoc •17·201201840 should be considered as not affecting sequence identity or homology. The variant retains the ability to bind to the variable domain of human TSLPR and preferably has properties superior to the parent antibody. For example, variants can have reduced side effects during processing. An "individual" or "subject" is a mammal. Mammals include, but are not limited to, dependent animals (eg, cows, sheep, cats, dogs, and horses), primates (eg, humans and non-human primates, such as monkeys), rabbits, and rodents. (eg, mice and rats). In certain embodiments, the individual or subject is a human.

The "separation" system is separated from the natural environmental components. In some embodiments, the antibody is purified to have greater than 95 Å/. Or 99% purity, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman, s et al., L.

Chromatogr. B 848 (2007) 79-87. "Isolated" nucleic acid refers to a nucleic acid molecule isolated from a natural environmental component. The isolated nucleic acid includes a nucleic acid molecule contained in a cell which usually contains a nucleic acid molecule, but the nucleic acid molecule exists extrachromosomally or exists at a chromosomal location different from its natural chromosomal location. "Isolated nucleic acid encoding an anti-TSLPR antibody" refers to one or more nucleic acid molecules encoding an antibody heavy and light chain (or a fragment thereof), including the nucleic acid molecule in a single vector or a separate vector, and present in a host The nucleic acid molecule at one or more positions in the cell. The term "nucleic acid" or "nucleic acid molecule" as used herein is intended to include DNA molecules and RNA molecules. The nucleic acid molecule may be single-stranded or double-stranded DNA, but is preferably 156874.doc • 18-201201840 double-stranded DNA. When a nucleic acid has a functional relationship with another nucleic acid, the core I is operably linked. For example, if the DNA of the pre-sequence or secretory leader sequence is expressed as a protein involved in polymorphism, the pre-sequence or the leader of the secretory leader can be operably linked to the DNA of the polypeptide; if the promoter or enhancer can affect the encoding The transcription of the sequence, the promoter or enhancer is operably linked to the coding sequence; or if the location of the ribosome binding site facilitates the transfer of the ribosome, the operably linked to the coding sequence By "operably linked" it is meant that the DNA sequences being linked are homologous and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers are not necessarily contiguous sequences. The connection can be made by connecting at a convenient restriction site. If such sites are not present, synthetic oligonucleotide adaptors or linkers are used according to conventional practice. As used herein, the expression "cell", "cell line" and "cell culture" are used interchangeably and all such names include progeny. Thus, the words "transformants" and plant transformed cells include primary subject cells and cultures derived therefrom without regard to the number of transfers. It should also be understood that the DNA content of all progeny may not be identical due to a specific or unintended mutation. The invention encompasses progeny that have been screened for variants of the same function or biological activity in the originally transformed cell.

I The term "package insert" is used to refer to the instructions generally included in the commercial product of a therapeutic product, which contains indications, usage, dosage, administration, combination therapy, contraindications and/or use of such therapeutic products. Information about the warning. An exemplary "parental" antibody comprises the CDR regions of antibody TSLP-012 and is preferably used to prepare variants. Preferably the 'parent antibody has a hamster framework region. Subsequently

I

' I 156874.doc · 1〇 201201840 Humanized parental antibodies. Examples of humanized antibodies derived from TSLP-0 12 are TSLPR-012_75, TSLPR-012_141, TSLPR-012_166, and TSLPR-012_189. The term "pharmaceutical formulation" refers to a formulation that is in a form that allows for the biological activity of the active ingredient contained therein to be effective and that does not contain additional components that are unacceptable to the subject to whom the formulation will be administered. "Pharmaceutically acceptable carrier" means a component of a pharmaceutical formulation that is not toxic to the individual other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. The term "specifically binds to TSLPR" as used herein means that the antibody and TSLPR-transfected human TSLPR (ACC 300, DSMZ, http://www.dsmz.de) on BA/F3 cells are at least ΙΟ·9 Μ·1. Preferably, the EC50 (FACS analysis) of ΙΟ·9 Μ·丨 to 10·12 结合·1 binds, but does not bind to untransfected BA/F3 (at 1 (no binding detected at the antibody concentration of Γ7 M·1). The thymic stromal lymphopoietin receptor (TSLPR, TSLP receptor, CLRF2, SwissProt Q9HC73) is a type I cytokine receptor subunit closely related to the common cytokine gamma chain (γ.). The TSLP system initiates and transports allergic immune responses. Interleukin (IL)-7-like cytokine. TSLP is mainly produced by epithelial cells and activated mast cells, and stimulates bone marrow dendritic cells (mDC), which are expressed by interleukin-7 (IL-7) alpha chain and A heterodimer composed of TSLP receptors. TSLP-activated mDCs can promote the differentiation of naïve CD4+ T cells into a Th2 phenotype and promote CD4+Th2 memory cell expansion. As used herein, "therapeutics" (and its grammatical variants, for example "treat" or "treating" refers to the clinical practice of changing the natural course of the individual being treated 1568 74.doc -20- 201201840 Pre- and may be administered for prophylactic purposes or during the course of clinical pathology. The desired effects of treatment include, but are not limited to, any direct or indirect pathology that prevents the onset or recurrence of the disease, alleviates the symptoms, and attenuates the disease. As a result, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state and alleviating or improving the prognosis. In some embodiments 'using the antibodies of the invention to delay the onset of disease or slow the progression of the disease β: "variable of the antibody of the invention" as used herein The domain (light chain variable structure 埤 (vL), heavy chain variable region (Vh)) represents each of the light chain and heavy chain domain pairs directly involved in the binding of the antibody to the antigen. Light and heavy chains The variable domains have the same general structure 'and each domain contains four highly conserved framework regions (FR)' which are linked via three "hypervariable regions" (or complementarity decisions 1$, CDRs). The β_fold conformation is used and cdr forms a ring that links the 丨3,-fold structure. Cdr in each chain maintains its three-dimensional structure by the framework region and forms an antigenic junction with the CDRs in the other chain. Binding point. Binding specificity/affinity of the CDR3 region of the antibody heavy chain and light chain in the antibody of the present invention

The aspect I has a particularly important role and thus provides a further object of the invention. The term "vector," as used herein, refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are included in the genome of the host cell into which they are introduced. Certain vectors are capable of directing the expression of a nucleic acid to which they are operably linked. Such vectors are referred to herein as "expression carriers." The antibodies of the invention are preferably produced by recombinant means. Such methods are well known in the art and are included in prokaryotic and eukaryotic cells to express egg 156874; doc 201201840 white matter and subsequent isolation of antibody polypeptides and are typically purified to a pharmaceutically acceptable purity. For protein expression, a nucleic acid encoding a light chain and a heavy chain or a fragment thereof is inserted into an expression vector by standard methods. Expressed in a suitable prokaryotic or eukaryotic host cell (eg, CHO cells, NSO cells, SP2/0 cells, HEK293 cells, COS cells, yeast, or E. coli cells), and from such cells (supernatant) The antibody is recovered by liquid or after lysis. Recombinant antibody production is well known in the art and is described, for example, in the following review article: Makrides, SC., Protein Expr. Purif. 17 (1999) 183-202; Geisse, S. et al., Protein Expr. Purif · 8 (1996) 271-282; Kaufman, RJ, Mol. Biotechnol. 16 (2000) 151-161; Werner, RG, Drug Res. 48 (1998) 870-880. Such antibodies may be present in intact cells, in cell lysates, or in partially purified or substantially pure form. Purification is performed by standard techniques to remove other cellular components or other contaminants, such as other cellular nucleic acids or proteins, including column chromatography and other methods well known in the art (see edited by Ausubel, F. et al. Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York (1987)). The performance in NS0 cells is described, for example, in the following literature: Barnes, LM et al. 'Cytotechnology 32 (2000) 109-123; Barnes, L., et al., Biotech. Bioeng. 73 (2001) 261- 270. The transient performance is described, for example, in Durocher, Υ· et al., Nucl. Acids. Res_ 30 (2002) Ε9. The selection of variable domains is described in Orlandi, R. et al., Proc. Natl. Acad Sci. USA 86 (1989) 3833-3837; Carter, Ρ· et al., Proc. Natl. 156874.doc -22- 201201840 乂cad. Sci. USA 89 (1992) 4285-4289 ; Norderhaug, L. et al., J. Immunol. Methods 204 (1997) 77-87 ° Preferred transient expression system (HEK 293) described in Schlaeger , E.-J. and Christensen, K., Cytotechnology 30 (1999) 71-83; & Schlaeger, E.-J., J.

Immunol. Methods 194 (1996) 191-199. Individual antibodies are isolated from the culture medium in a suitable manner by conventional immunoglobulin purification procedures, such as protein A-agarose method, hydroxyapatite chromatography, gel electrophoresis, dialysis or affinity chromatography. The DNA and RNA encoding the monoclonal antibodies can be easily isolated and sequenced using conventional procedures. Hybridoma cells can be used as a source of JtDNA and RNA. After isolation, the DNA can be immediately inserted into the expression vector' and subsequently transfected into a host cell (such as HEK 293 cells, CHO cells or myeloma cells) that does not produce immunoglobulin to achieve recombinant growth in the host cell. Synthesis of antibodies. Preferred embodiments of the invention are obtained from such cell lines. Amino acid sequence variants of human TSLPR antibodies are prepared by introducing appropriate nucleotide changes into the antibody encoding the DNA or by peptide synthesis. However, such modifications can be carried out to a very limited extent as described, for example, above. For example, the ii s s-thin modification does not alter the above-described antibody properties, such as IgG isotype and epitope β binding, but can improve recombinant yield, protein stability, or favorable purification. Any cysteine residue that does not participate in maintaining the proper conformation of the anti-TSLPR antibody can also typically be substituted with a serine to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, a cysteine bond can be added to the antibody to improve its stability (especially a right anti-system antibody fragment such as an F ν fragment). Another type of amino acid variant of an antibody alters the initial glycosylation pattern of the antibody. 156874.doc -23-201201840 "Change" means removal of one or more carbohydrate moieties found in one or more carbohydrate moieties found in an antibody and/or in an added antibody. Glycosylation of antibodies is usually N-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an indoleamine residue. Tripeptide sequence aspartame χ χ 丝 丝 丝 及 天 天 天 天 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝Attached identification sequence. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. The glycosylation site is conveniently added to the antibody by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for a guanidine-linked glycosylation site). Nucleic acid molecules encoding amino acid sequence variants of an anti-TSLPR antibody are prepared by a variety of methods known in the art. Such methods include, but are not limited to, isolation from a natural source (provided to be a naturally occurring amino acid sequence variant) or recruitment of a humanized anti-TSLPR antibody by a previously prepared variant or non-variant form Prepared by mediation (or site-directed mutagenesis), PCR mutagenesis, and cassette mutagenesis. Another type of covalent modification of an antibody comprising one of a plurality of non-proteinaceous polymers (e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylene) is disclosed in U.S. Patent Nos. 4,640,835, 4,496,689, Linking in the manner described in 4,301,144, 4,670,417, 4,791,192, 4,179,337. The heavy and light chain variable domains of the present invention are linked to a promoter, translation initiation, constant region, 3' The sequences of the non-translated regions, polyadenylation, and transcription termination are combined to form an expression vector construct. Heavy and light chain expression constructs 玎 156874.doc -24· 201201840 Synthetic single-vectors, co-transfected, serially transfected or individually transfected into host cells, then fused to form a single host representing both strands cell. In another aspect, the invention provides a composition, such as a pharmaceutical composition comprising a monoclonal antibody or a monoclonal antibody of the invention, or an antigen binding portion thereof, formulated with a pharmaceutically acceptable carrier together. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption/resorption delaying agents, and is physiologically compatible. Similar agent. Preferably, the carrier is suitable for injection or infusion. The compositions of the present invention can be administered by a variety of methods known in the art. As will be appreciated by those skilled in the art, the route of administration and/or manner 2 will vary depending on the desired result. Pharmaceutically acceptable carriers include sterilized water: liquid or dispersion', and sterilized injectable solutions or dispersions for the preparation of sterilized injectable solutions or dispersions. . In addition to water, the carrier can be, for example, a buffered saline solution. Administration Routes Not Selected by S The compounds of the present invention and/or the pharmaceutical compositions of the present invention which may be suitably used in a hydrated form are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an active ingredient which is effective in achieving the desired therapeutic response in a patient, composition and mode of administration without the amount of the agent (effective amount). The selected dose will depend on a variety of pharmaceutical motivating factors, including the activity of the particular composition used in the present invention, the route of administration, the rate of excretion of the particular compound employed, and other drugs, compounds and/or compounds employed in the particular compositions employed. Materials, age, sex, weight, condition, general health and prior medical history of the patient being treated, and medicine 156874.doc • 25. 201201840 Similar factors well known in the art The present invention comprises antibodies of the invention for use in treating patients suffering from immune diseases the use of. The invention further provides a method of making a pharmaceutical composition comprising an effective amount of an antibody of the invention and a pharmaceutically acceptable carrier, and the use of an antibody of the invention in such a method. The invention further provides for the use of an effective amount of an antibody of the invention, preferably in combination with a pharmaceutically acceptable carrier, for the manufacture of a pharmaceutical agent for the treatment of an immune disorder, particularly asthma, atopic dermatitis or rheumatoid Patients with arthritis. The invention also provides for the use of an effective amount of an antibody of the invention, preferably together with a pharmaceutically acceptable carrier, for the manufacture of a pharmaceutical agent for the treatment of a patient suffering from an immune disorder. Recombination method and composition

Recombinant methods and compositions can be used to produce antibodies, for example, as described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-TSLPR antibody described herein is provided. The nucleic acid may encode an amino acid sequence comprising VL in the antibody and/or an amino acid sequence comprising VH (e.g., a light bond and/or a heavy bond of an antibody). In another embodiment, one or more vectors (e.g., expression vectors) comprising the nucleic acid are provided. In another embodiment, a host cell comprising the nucleic acid is provided. In one such embodiment, the host cell comprises (eg, has been transformed with such a substance): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amine group comprising the VH of the antibody An acid sequence, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody, and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the antibody VH 156874.doc -26-201201840 . In one embodiment, the host cell line is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (eg, Υ0, NS0, Sp2〇 cells). In one embodiment, a method of making an anti-TSLPR antibody is provided. Wherein the method comprises culturing a host cell comprising a nucleic acid encoding an antibody as set forth above, and recovering the antibody from the host cell (or host cell culture medium), as appropriate, under a modification suitable for expression of the antibody. For recombinant production of an anti-TSLPR antibody, the nucleic acid encoding the antibody (eg, as described in the previous year) is isolated and inserted into one or more vectors to further colonize and/or express in the host sputum. The nucleic acid can be readily used using conventional procedures. Is isolated and sequenced (e.g., by using an oligonucleotide probe that is capable of specifically binding to a gene encoding the heavy 4 and light chain of the antibody). Suitable host cells for the selection or expression of vectors encoding the antibodies include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required, for the performance of antibody fragments and polypeptides in bacteria, for example, see U.S. Patent Nos. 5,648,237, 5,789,199. And No. 5,840,523 (see also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Hiimana Press, Totowa, NJ, 2003), pp. 245-254, which illustrates the performance of antibody fragments in E. coli). After performance, the antibody can be isolated as a soluble fraction from the bacterial cell slurry and can be further purified. | : In addition to prokaryotes, eukaryotic microorganisms (such as filamentous fungi or yeast) are also suitable

I. Use of a fungal or yeast strain for the selection or expression of a host for encoding an antibody, including antibodies whose glycosylation pathway has been "humanized" to produce a partial or complete human glycosylation pattern. See Gerngross, T.U., Nat. 156874.doc •27- 201201840

Biotech. 22 (2004) 1409-1414 and Li, et al., Nat. Biotech. 24 (2006) 210-215 适宜 Suitable host cells for expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates) And vertebrates). Examples of invertebrate cells include plant and insect cells. A variety of baculovirus strains have been identified for use in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures can also be used as hosts. For example, see U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429, which are incorporated herein by reference. The cell acts as a host. For example, mammalian cell lines suitable for growth in suspension can be used. Other examples of useful mammalian host cell lines are the SV40 transformed monkey kidney CV1 cell line (COS-7); the human embryonic kidney cell line (293 cells or, for example, Graham, FL et al., J. Gen Virol. 36). (1977) 293 cells described in 59-74); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells such as, for example, Mather, JP, Biol. Reprod. 23 (1980) 243-252); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); Buffalo rats (buffalo rat) hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); TRI cells (eg (eg) Mather, JP et al., Annals NY Acad. Sci. 383 (1982) 44-68); MRC5 cells; and FS4 cells. Other useful 156874.doc •28· 201201840 Mammalian host cell lines include Chinese hamster ovary (CHO) cells, including lHFR-CHO fine moon packs (Urlaub et al, Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220); and myeloma cell lines, such as Y〇, NSO and

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Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, for example, see 'Yazaki, P.J. and Wu, A.M., Methods in Molecular Biology, Antibody Engineering: Methods and

I {protocols ' Vol. 248 (BKC Lo (ed.), Humana Press, Totowa, NJ), (2004), pp. 255-268 ° Renal Formulations The pharmaceutical formulations of the anti-TSLPR antibodies described herein are by mixing The antibody having a purity of one stage and one or more pharmaceutically acceptable optional carriers (Osol, A. (ed.), Remingt〇n's Pharmaceutical Sciences, 16th Edition, (1980)) as a lyophilized formulation or aqueous solution Form is made. Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the dosages and concentrations employed, and include, but are not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and sulphur Aminic acid; preservative (for example, octadecyldidecylbenzylammonium hydride; hexamethylene diammonium chloride; benzalazine, benzathine; benzoquinone, butanol or benzofuran; Benzoic acid-based vinegar, such as decyl hydroxybenzoate or propyl p-hydroxybenzoate; catechol, m-phenylene; cyclohexanol; 3-pentanol; and m-cresol; Molecular weight (less than about 10 residues) polypeptide; protein, such as serum albumin, gelatin or immunoglobulin; hydrophilic polymer, such as polyvinyl ruthenium <! each. Amino acid, such as glycine, glutamine, aspartame, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including grapes 156874.doc - 29-201201840 Sugar, mannose or dextrin; chelating agents, such as EDTA; sugars, such as curtain sugar, mannitol 'haitose or sorbitol; salt-forming counterions, such as sodium'; metal complexes (eg Zn- Protein complex); and/or nonionic surfactants such as polyethylene glycol (PEG). An exemplary pharmaceutically acceptable carrier herein includes an interstitial drug dispersing agent, such as a soluble neutral active hyaluronidase glycoprotein (sHASEGP), for example, a human soluble pH 20 hyaluronidase glycoprotein For example, rHuPH2〇 (HYLENEx8,

Internati〇nal company). Some example sHASEGPs and methods of use (including rHuPH20) are described in U.S. Patent Publication Nos. 2, 5/26, 186 and 2, 6/1, 4, 968. In one aspect, sHASEGp is combined with one or more additional glycosaminoglyases (e.g., chondroitinase). Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent Nos. 6, i7i, 586 and WO 2006/044908, the latter formulation comprising a histidine acetate buffer. The formulations of the present invention may also optionally contain more than one active ingredient for the particular indication being treated, preferably those having complementary effects that do not adversely affect each other. These active ingredients are suitably present in combination in amounts which are intended to achieve the desired effect. The active wound may also be incorporated into microcapsules prepared by, for example, coacervation techniques or interfacial polymerization (eg, 'methylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules), Glial drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. These techniques are disclosed in 〇s〇I, Α (ed.) I56874.doc 201201840

Pharmaceutical Sciences, 16th Edition (1980). Can be made into a sustained release preparation. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing antibodies, which are in the form of shaped articles, for example, films or microcapsules. Formulations intended for/in vivo administration are usually sterile. Sterility can be easily achieved, for example, by filtration using a sterile filtration membrane. Methods of Treatment and Compositions Any of the anti-TSLPR antibodies provided herein can be used in a method of treatment. I · In one aspect, an anti-TSLPR antibody for use as a medicament is provided. In other aspects, anti-TSLPR antibodies are provided for the treatment of diseases characterized by activation by TSLPr, preferably immune diseases (especially asthma, atopic dermatitis or rheumatoid arthritis). In certain embodiments, an anti-TSLPR antibody for use in a method of treatment is provided. In certain embodiments, the invention provides an anti-TSLPR antibody in a method for treating an individual, the subject having a disease characterized by activation of ΊSLPR activation, preferably an immune disease (especially asthma, atopic dermatitis or Rheumatoid arthritis), the method comprising administering to the individual an effective amount of an anti-TSLPR antibody. In one embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, for example, Said. In other embodiments, the invention provides an anti-TSLPR antibody for use in a disease modulated by TSLpR activation. In certain embodiments, the invention provides an anti-TSLPR antibody in a method for treating a disease mediated by activation of TSLPR, the method comprising administering to the individual an effective amount of an anti-T$LPR antibody to modulate TSLPR activation. 156874.doc •31-201201840 “individual” is preferred to humans in any of the above embodiments. "In another aspect, the invention provides the use of an anti-TSLPR antibody in the manufacture or preparation of a medicament. In one embodiment, the medicament is for the treatment of a disease, preferably an immune disorder (especially asthma, atopic dermatitis or the like) Rheumatoid arthritis). In another embodiment, the method is for treating a disease, preferably an immune disease (especially asthma, atopic dermatitis or rheumatoid arthritis), the method comprising The individual of the disease is administered an effective amount of the agent. In this embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent', eg, as described below. In yet another embodiment, the agent In a method for treating an individual, the method comprises administering to the individual an effective amount of an agent to modulate TSLPR activation. The "individual" of any of the above embodiments can be a human. In still another aspect, the invention provides methods of treating an immune disorder, particularly asthma, atopic dermatitis or rheumatoid arthritis. In one embodiment, the method comprises administering to an individual having the immune disease (especially asthma, atopic dermatitis or rheumatoid arthritis) an effective amount of an anti-"foot antibody. In the embodiment, The method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, as described below. The "individual" of any of the above embodiments can be a human. In still another aspect, the invention provides a method of administering to a subject an effective amount of an anti-TSLPR antibody of the invention to treat an immune disease, particularly asthma, atopic dermatitis or rheumatoid arthritis. In one embodiment, the "individual" is a human. In yet another aspect, the invention provides a pharmaceutical formulation comprising any of the 156874.doc • 32-201201840 7 anti-TSu>R antibodies herein, for example, for use in any of the above methods of treatment in. In one embodiment the 1 drug formulation comprises any of the anti-TSLPR antibodies provided herein and is pharmaceutically acceptable (4). In another embodiment the 'pharmaceutical formulation comprises any one of the WR antibodies provided herein and at least one additional therapeutic agent, for example, as described below. The anti-caries of the present invention can be used in therapy alone or in combination with other agents. For example, a single statement can be administered in combination with an antibody of the invention and at least one additional therapeutic agent. The combination therapy referred to above encompasses combination administration (in which two or more agents are included in the same or separate formulation), and separate administration (in this case, the administration of the antibody of the present invention can be Where additional therapeutic agents and/or adjuvants are administered, simultaneously, and/or afterwards). The antibodies of the invention (and any additional therapeutic agents) can be administered by any suitable means including parenteral, intrapulmonary and intranasal, and (if desired for topical treatment) intralesional administration. Parenteral infusion includes intramuscular, intravenous, and arterial intraperitoneal or subcutaneous administration. Administration can be by any suitable route, exemplified by injection, e.g., intravenous or subcutaneous injection, depending in part on the length of administration. This article covers a variety of dosing regimens including, but not limited to, single or multiple doses, bolus doses, and pulse infusions at different time points. The antibodies of the invention should be formulated, adjusted and administered in a manner consistent with good medical practice. In this case, considerations include the particular condition being treated, the particular condition being treated, the particular condition of the individual patient, the clinical condition of the individual patient, the cause of the condition, the agent, the site of delivery, the method of administration, the time of administration, and the medical condition. Other factors known to the industry. The antibody need not (but as needed) be formulated with one or more agents currently used to prevent or treat the disorder in question. The effectiveness of these other remedies

I 156874.doc -33- 201201840 Depending on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. Such agents are typically administered in the same dosages and in the administration routes described herein, or from about 1% to 99% of the dosages described herein, or in any suitable dosage or any route determined empirically/clinically. For the prevention or treatment of a disease, a suitable dose of the antibody of the invention (when used alone or in combination with one or more other therapeutic agents) should be considered as the type of disease to be treated, the type of antibody, the severity and duration of the disease, and the regime of administration. It is used for prophylactic or therapeutic purposes, prior therapy, clinical history of the patient, response to antibodies, and discretion of the attending physician. The antibody is suitable for administration to a patient once or via a series of treatments. Depending on the type and severity of the disease 'about 1 pg/kg to 15 mg/kg (eg 〇.1 mg/kg to 1 〇 mg/kg) the antibody may be the initial candidate dose for administration to the patient, for example one or more times Individually administered or continuously infused. Depending on the above factors, a typical daily dose can be about t

It is in the range of Mg/kg to 1 〇〇 mg/kg or higher. For repeated dosing for a few days or longer, depending on the condition, the treatment usually continues until the desired repression of the disease symptoms occurs. An exemplary dosage of an antibody can range from about 〇5 paws "" to about 10 mg/kg. Thus, one or more doses of about 5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or a combination thereof) can be administered to a patient. Such doses can be administered intermittently, such as once a week or once every three weeks (e.g., such that the patient receives from about two to about two, or, for example, about six doses of the antibody). One initial higher loading dose can be administered followed by one or more lower doses. The progress of this therapy is easily monitored by techniques and analysis. It will be appreciated that the immunoconjugate of the invention can be used in place of the anti-antibody I56874.doc • 34-201201840 of the above formulation or treatment or with an anti-TSLPR antibody.

I Article ▲ In another aspect of the invention, an article comprising a material for treating, preventing and/or diagnosing the above conditions is provided. The article comprises a container and a label or package insert located adjacent to the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be of various materials such as glass or plastic. Formed. The container comprises a composition that is effective in treating, preventing, and diagnosing a condition when combined with itself or in combination with another agent' and may have a sterile access channel (eg, the container may be an intravenous solution bag or have a vial of a stopper pierced by a hypodermic needle. The active agent of the composition is an antibody of the invention. The label or package insert indicates that the sample is used to treat the selected condition. In addition, the article The invention may comprise (4) a first-barrage comprising a mouthpiece, the composition comprising the antibody of the invention; and (8) a second container comprising the composition, wherein the composition comprises an additional cytotoxic agent or therapeutic agent. The article of this embodiment may further comprise a package insert indicating that the composition is useful for treating a particular condition. Alternatively or additionally, the article may further comprise a second (or third) container, the container Containing a buffer of pharmaceutically acceptable β Γ 丈, such as bacteriostatic water for injection (B WF] [), phosphate buffered saline, Ringer's solution (Ringer, ss〇luti〇n) and dextrose solution. This includes other materials that are desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. It is understood that any of the above products may include an immunoconjugate of the present invention instead. Anti-TSLPR antibodies or used with anti-TSLPR antibodies. 156874.doc -35- 201201840 The following are examples of the methods and compositions of the present invention. It should be understood that various other embodiments can be practiced in light of the general description provided above. The above description of the invention has been described in some detail by way of illustration and example, but the description and examples should not be construed as limiting the scope of the invention. The disclosure of all patents and scientific documents cited herein is incorporated by reference. The manner is expressly incorporated herein. Sequence Listing Description SEQ ID NO: 1 Sequence TSLPR-012 (hamster) HC variable region SEQ ID NO: 2 hCDR1 TSLPR-012 SEQ ID NO: 3 hCDR2 TSLPR-012 SEQ ID NO: 4 hCDR3 TSLPR-012 SEQ ID NO: 5 sequence TSLPR-012 (hamster) LC variable region SEQ ID NO: 6 1 CDR1 TSLPR-012 SEQ ID NO: 7 1 CDR2 TSLPR-012 SEQ ID NO: 8 1 CDR3 TSLPR-012 SEQ ID NO: 9 SEQ ID NO: 81^11-012_141 (humanization) 11 (: variable region SEQ ID NO: 2 hCDR1 TSLPR-012_141 SEQ ID NO: 10 hCDR2 TSLPR-012_141 SEQ ID NO: 4 hCDR3 TSLPR-012_141 SEQ ID NO: 11 SEQ ID NO: 81^11-012_141 (humanized) 1^ variable region SEQ ID NO: 12 1 CDR1 TSLPR-012_141 SEQ ID NO: 13 1 CDR2 TSLPR-012_141 SEQ ID NO: 8 1 CDR3 TSLPR -012_141 SEQ ID NO: 9 Sequence TSLPR-012_75 (humanized) HC variable region 156874.doc -36-201201840 SEQ ID NO: 2 hCDR1 TSLPR-012_75 SEQ ID NO: 10 hCDR2 TSLPR-012_75 SEQ ID NO: 4 hCDR3 TSLPR-012_75 SEQ ID NO: 14 Sequence TSLPR-012_75 (humanized) LC variable region SEQ ID NO: 12 1 CDR1 TSLPR-012_75 SEQ ID NO: 15 1 CDR2 TSLPR-012_75 SEQ ID NO: 8 1 CDR3 TSLPR-012_75 SEQ ID NO : 16 sequence TSLPR-012_166 (humanized) HC variable region SEQ ID NO: 17 hCDR1 TSLPR-012_166 SEQ ID NO: 10 hCDR2 TSLPR-012_166 SEQ ID NO: 4 hCDR3 TSLPR-012_166 SEQ ID NO: | 18 Sequence TSLPR-012_166 (humanized) LC variable region SEQ ID NO: 12 1 CDR1 TSLPR-012_166 SEQ ID NO: 15 1 CDR2 TSLPR-012_166 SEQ ID NO: 8 1 CDR3 TSLPR-012_166 SEQ ID NO: 9 sequence TSLPR-012_189 (humanized) HC variable region SEQ ID NO: 2 hCDR1 TSLPR-012_189 SEQ ID NO: 10 hCDR2 TSLPR-012_189 1 SEQ ID NO: 4 hCDR3 TSLPR-012_189 SEQ ID NO: 19 Sequence TSLPR-012_189 (humanized) LC variable region SEQ ID NO: 1 12 1 CDR1 TSLPR-012_189 SEQ ID NO: 7 1 CDR2 TSLPR-012_189 SEQ ID NO: 8 1 CDR3 TSLPR-012_189 SEQ ID NO: 20 Sequence Human Ig γΐ (G1M1 , 17) 156874.doc -37-201201840 SEQ ID NO: 22 Sequence Human Ig γ4 SEQ ID NO: 22 Sequence Human Ig γ4 (S228P, L235E) SEQ ID NO: 23 Sequence Human Ig κ Example 1 Immunization Description Immunization with Human TSLPR Armenian hamsters with 50 pg recombinant human soluble TSLPR-Fc fusion protein (TSLPR amino acid 23 to 231) and complete Freund's adjuvant (on day 0) and incomplete Freund's adjuvant (at 28, 56) , 84 and 112 days) immunization of Armenian warehouse by intraperitoneal injection . Blood was collected on days 91 and 119 and serum was prepared for potency determination by ELISA and proliferation assay (see below). The animals with the highest titer were selected for boosting immunity by intravenous injection of 50 Mg recombinant human soluble TSLPR-Fc fusion protein on day 140, and antibodies were isolated. The antibodies of the invention were identified by binding to human TSLPR, binding to BA/F3-TSLPR/IL7Ra and Cyno-TSLPR-HEK293 cells in a FACS assay. Example 2 Binding of human TSLPR antibodies to human TSLPR was determined by ELISA in conjunction with human TSLPR (ELISA). Human recombinant TSLPR-Fc was fixed to 384-well Nunc Maxisorp plates in PBS at 150 ng/ml, 25 μΐ/well by overnight incubation at 2 °C to 8 °C. After washing each well four times with 90 μM PBST (0.1% Tween® 20 'preserved in PBS), the plate was blocked with PBS/1% BSA for 1 h at room temperature followed by four wash steps (PBST) And incubated with different concentrations of anti-156874.doc -38-201201840 TSLPR antibody in blocking buffer or fusion tumor supernatant for 1 h at room temperature » After washing four more times, use antibody at room temperature for 1 : 5000 anti-hamster-HRP antibody diluted in blocking buffer for 1 h. After another four washing steps, ABTS® (Roche Diagnostics GmbH) was added and the signal was generated for 10 to 30 minutes. The absorbance was read at 4 〇 5 nm. Example 3

Combination of I with BA/F3-TSLPR/IL7Ra and Cyno-TSLPR-HEK293 cells (FACS)

I1 demonstrates the binding of anti-TSLPR antibodies to cells expressing TSLPR by FACS using BA/F3 cells stably expressing human TSLPR, and using the diet

I simian TSLPR transiently transfected HEK293 cells to confirm the binding of IL_7Ra to cynomolgus TSLPR. Make BA/F3-TSLPR/IL7Ra or Cyno-TSLPR-

I Ή (ΕΚ293 cells without TSLP overnight, harvested by centrifugation, washed once in PBS and resuspended in FACS buffer (PBS/5% FCS) at 106/ml. 100 μΐ cell suspension with 100 μΐ anti-TSLPR The antibody solution was incubated for 45 minutes on ice in a 96-well round bottom well. After washing with FACS buffer, the cells were resuspended in PE-conjugated anti-hamster-F(ab)2 (1:200, buffered in FkcS). The solution was incubated on ice for 30 minutes. After washing three times, the cells were resuspended in 200 μF FACS buffer and measured on a FACS Canto flow cytometer (10,000 cells, flow rate 3). Example 4 Blocking BA/F3-TSLPR/IL7Ra proliferation Add 30 μΐ of the fusion tumor supernatant or anti-ThPR antibody solution to the wells of a 384-well white plate (antibody of the invention and antibody of WO 2007/112146 156874.doc • 39·201201840 1D6.C9), after adding 20 μΐ of BA/F3 cells stably expressing human TSLPR and IL-7Ra, which were suspended at a density of 25,000 cells/1111 in a growth medium without butyl 81% (RPMI/10% FCS) After incubation for 1 h at 37 ° C / 5% C02, add 10 μΐ TSLP solution to 1 ng/ml. Degree. The cells at 37 ° C / 5% C02 incubated 48 h, then was added to each well reagent 20 μΐ CellTiter-Glo® mixture was shaken and the reading luminance 2 min.

Example S Blocking TSLP/TSLPR/IL7Ra interaction in ELISA Recombinant human TSLPR-Fc was coated by incubating a solution of 50 μΐ 0.2 pg/ml TSLPR-Fc in PBS in PBS for 1 h at RT. On a 96-well Nunc Maxisorp plate well. Subsequently, the wells were blocked with 1% Crotein C (blocking buffer) in PBS for 1 h at RT, followed by washing twice with washing buffer (ice-cold PBS/0.05% TWEEN® 20). Subsequently, 50 μM anti-TSLPR antibody solution (the antibody of the present invention and WO 2007/112146) was added to the well and incubated at 4 ° C for 2 h, followed by four washing steps. After adding human recombinant TSLP (12.5 ng/ml) and human recombinant IL7Ra-Fc (1 pg/ml) in a 50 μΐ mixture in blocking buffer, the plate was shaken at 4 ° C for 1 h, and then again One or four washing steps. Incubate with 50 μM biotinylated anti-TSLP antibody (0.08 pg/ml in blocking buffer) per well, followed by four washes and 50 μM streptavidin-HRP (0.25 pg/) Ml, stored in blocking buffer) was incubated together to detect TSLP binding. After another four washing steps, color was formed by incubation with 50 μM of 3,3,5,5-tetradecylbenzidine, followed by addition of 50 μl of HCl. The absorbance was read at 450 nm and 620 nm. 156874.doc -40-201201840 Example 6 Determination of Affinity of Antibody-TSLPR Complex Using Biacore The binding of a single anti-TSLPR antibody of the present invention and WO 2007/112146 was analyzed by surface plasmon resonance (SPR) technique using a Biacore 3000 instrument. nature. Affinity is determined using an assay setup with capture antibodies. These capture antibodies (goat anti-human-IgG, goat anti-hamster: [gG) were immobilized on the surface of the CM5 biosensor wafer using amine coupling _chemistry. The capture antibody was injected at a concentration of 5 pg/ml in sodium acetate buffer (pH 5.0) to achieve a surface density of about 1000 RU. The remaining reactive groups were inactivated by injection of 1 hydrazine ethanol/HC1 pH 8_5. The running buffer is HBS-P. The anti-TSLPR anti-sputum (analyte 1) was diluted in HBS-P to a concentration of 25 nM and injected at a rate of 5 μΐ/min for 3 minutes to end-produce the binding signal of 100-400 RU. The extracellular domain of TSLPR obtained by cleavage of the TSLPR-Fc fusion protein (analyte 2) expressed in sputum cells at a concentration ranging from 0 nM to 50 nM at a flow rate of 20 μΐ/min (ie TSLPR) -ECD) » The contact time (association period) of TSLPR is 3 min, then the dissociation time is “5 minutes. After each combination cycle, the flow rate is 10 μΐ/min for 1 min.

I Two injections of regeneration solution (10 mM glycine HCl (pH 1.5) or 1 mM mM Glycine

I acid HCl (pH 1.7)) to remove any binding proteins. All interactions were carried out at 25 ° C (standard temperature). The 1 signal is detected at a detection rate of 1 signal/second. Subtract the signal from the reference flow unit (FC1: same capture antibody and add control antibody) and blank buffer injection and evaluate the data. Fit all combined curves: lines to a 1:1 Langmuir binding model. From this, the association rate constant (ka), the dissociation rate constant (kd), and the dissociation equilibrium constant (KD) were calculated. 156874.doc -41 - 201201840 Example 7 Inhibition of CDllc+ DC TARC secretion The secretion of TARC/CCL17 and related cytokines by CDllc+ dendritic cells (DC) may indicate that DCs are activated by TSLP, ultimately leading to TH2 differentiation in asthma and atopic dermatitis. . TARC secretion blocked by the anti-TSLPR antibody of the present invention and including 1D6.C9 (WO 2007/112146) was measured on the supernatant of TSLP-activated CDllc+ DC using ELISA. The CDllc+ DC system is basically prepared by Soumelis et al., Nature Immunol. 7, 673-680 (2002) from peripheral blood mononuclear cells (PBMC) by using magnetic beads to deplete the expression line markers. Cells of CD3, CD14, CD19, CD56 and glycophorin A, followed by FACS-screening of CDllc+ cells. DCs were cultured in RPMI with 10% FCS, 1% pyruvate, 1% HEPES, and penicillin/streptomycin, pre-incubated with anti-TSLPR antibodies at various concentrations and stimulated with 15 ng/ml TSLP for 48 hours. TARC was measured in DC supernatants using a commercially available human TARC ELISA. All antibody concentrations mentioned in this patent application are related to the molecular weight of the antibody of 150.000. Examples of Examples 4, 5, 6 and 7 are shown in Table 1. The results of Example 3 are shown in Table 2. TSLP-induced inhibition of CD80, CD86, MDC, eosinophilin, eosinophilin 3, MIP-Ιβ and IP10 was observed (data not shown). 156874.doc •42· 201201840 Table 1: 1 Antibody 1 IC50 proliferation (Example 4) [ng/ml] IC50 ELISA (Example 5) [ng/ml] BIAcore affinity (Example 6) KD [ΙΟ·9 M] IC50 DC analysis (Example 7) ing/mll 1D6.C9 (W02007/ 112146) 84 15.2 2.97 nd TSLPR-012_75 » CDR transplantation 26 13.4 0.50 42 TSLPR-01: 2 141, CDR transplantation 37 10.4 0.87 46 1 TSLPR-012_166 , cbR transplantation 34 12.2 2.45 86 TSLPR-012J89 > CDR Transplantation 25 13.6 0.60 23 TSLPR-012 26 8.8 0.25 129 Table 2 (Example 3): Antibody 1 EC50 FACS BA/F3-TSLPR/IL7Ra[ng/mll EC50 FACS HEK-Cyno- TSLPR[ng/mll TSLPR-012_75 » CDR transplantation 15.7 10.8 TSLPR-012_141 » CDR transplantation 13.3 9.7 TSLPR-012_166 > CDR transplantation 11.8 8.6 TSLPR-012_189, CDR transplantation 14.9 10.3 TSLPR-012 15.6 11.8 156874;d〇c •43 • 201201840 Example 8 Inhibition of dendritic cell (DC) activation The ability of the antibodies of the invention to block dendritic cell activation (including TARC, MDC, IL-8 secretion and CD80 and CD86 on the cell surface) was tested. For this purpose, human dendritic cells were isolated from peripheral blood and stimulated with 10 ng/ml TSLP in the presence or absence of antibodies. After 48 hours of incubation, cytokines and surface markers were measured. The antibody produces a concentration-dependent inhibition of the reaction. For TARC, for example, for the anti-TSLPR antibody TSLPR-012_141, the average IC50 soil SE > ^ 2.4 nM. For the anti-TSLPR antibody TSLPR-012_141, the IC50 range for all reactions is between 1·7ηΜ and 5·9ηΜ. Example 9 Inhibition of Th2 Cytokine Production in Polarization Analysis DCs activated with TSLP have been shown to promote the differentiation of naive T cells into a Th2 phenotype. To test the ability of the antibodies of the invention to block this process, DCs were stimulated with TSLP in the presence and absence of antibodies. It was then co-cultured with naive T cells under Th2 differentiation conditions. When the naive T cells were cultured with TSLP-activated DCs, the secretion of the Th2 cytokines IL-13 and IL-5 was observed. Dose-dependent inhibition of IL-13 (see also Figure 1) and IL-5 production was observed when DCs were activated in the presence of different concentrations of antibodies. The anti-TSLPR antibody TSLPR-012_141 has an IC50 of 2.57 nM for IL-13 release and 1.62 nM for IL-5. Example 10 Inhibition of mast cell cytokine release Tests using human mast cell culture derived from CD34+ hematopoietic stem cells 156874.doc -44 - 201201840 The ability of the antibodies of the invention to inhibit TSLP-induced mast cell cytokine production. The cells were incubated for 8 weeks and stimulated with IL-4 for 5 days prior to analysis. Cells were incubated with different concentrations of antibody or antibody control for 1 hour and subsequently stimulated with TSLP in combination with IL-lp/TNFa or IL-33. IL-13, • [L-5 and GMCSF analysis of the analysis. The anti-TSLPR antibody TSLPR-012 141 effectively inhibits the production of cytokines by mast cells when stimulated with TSLP in combination with IL-ip/TNFa or IL-33. Experiments were repeated with 3 different cultures from different donors. The average IC50 range for these experiments is between 0.04

I nM to 0.06 nM. [Simple description of the map]

I Figure 1 Inhibition of Th2 cytokine production by anti-TSLPR antibody TSLPR-012_141 in polarization analysis. 156874.doc -45- 201201840 SEQUENCE LIST <110> Swiss company Herfoe Menglaro Co., Ltd. <120> Antibodies that specifically bind human TSLPR and methods of use thereof

<130> 26828 FT <140> 100124817 <Ul> 2011-07-13 <150> EP10169728.2 <151> 2010-07-15 Seven 160> 23 <170> Patentln version 3.5

0 12 3 1 X 1 1 2 2 2 2 V V V V 122

PRT Grey Hamster <400> 1

Gin lie Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Phe Ser lie Thr Thr Ser 20 25 30

Qly Tyr Tyr Trp Thr Trp lie Arg Gin Phe Pro Gly Lys Lys Leu Glu 35 40 45 T:rp Met Gly Tyr lie Gly Tyr Asn Ser Lys Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg worker le Ser lie Thr Arg Asp Thr Ser Lys Asn Gin Phe 55 70 75 . 80

Leu Leu His Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr I 85 90 95

Cys Ala Arg Ser Leu Tyr Gly Gly Tyr Lys Asp Ala Phe Asp Ser Trp i 100 105 110

Gly. Gin Qly Thr Leu Val Thr Val Ser Ser 1 115 <:210> 2 <:211> 12 <212> PRT <:213> Grey Hamster I..- _ Λ Λ 156874彳 Sequence Listing.doc · 201201840 <400> 2

Gly Phe Ser lie Thr Thr Ser Gly Tyr Tyr Trp Thr 1 5 10 <210> 3 <211> 16 <212> PRT <213> Grey Hamster <400> 3

Tyr lie Gly Tyr Asn Ser Lys Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210> 4

<211> 12 <212> PRT Grey Hamster <400> 4

Ser Leu Tyr Gly Gly Tyr Lys Asp Ala Phe Asp Ser IS 10 <210> 5 <211> 108 <212> PRT <213> Grey Hamster <400>

Asp Val Val Leu Thr Gin Thr Pro Ala Thr Leu Ser Ala lie Pro Gly 15 10 15

Glu Arg Val Thr Met Thr Cys Lys Ala Ser Gin Ser lie Gly Thr Ser 20 25 30

Leu His Trp Tyr Gin His Arg Pro Asn Glu Thr Pro Arg Leu Leu lie 35 40 45

Lys Phe Ala Ser Arg Ser lie Thr Gly lie Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Gly lie Asn Asn Leu Glu Ala 65 70 75 80

Glu Asp Phe Ala He Tyr Tyr Cys Gin Gin Ser Pro Gly Phe Pro Pro 85 90 95 156874 · Sequence Listing.doc 201201840

Thr Phe Gly Ser Gly Thr Lys Leu Glu lie Asn Arg ! 100 105 <210> 6 <211> 11 <212> PRT Grey Hamster <400> 6

Lys Ala Ser Gin Ser lie Gly Thr Ser Leu His 15 10 <210> 7 <211> 7

<212> PRT U13> Grey Hamster <400> 7

Phe Ala Ser Arg Ser lie Thr 1 5 ς210> 8 <211> 9 <212> PRT <213> Grey Hamster < 4 0 0 > 8

Gin Gin Ser Pro Gly Phe Pro Pro Thr 1' - 5 <210> 9 <211> 122 <:212> PRT Artificial C: 2 2 0 > Sequence TSLPR-012_141 (Humanized) HC Variable Region <;:400> 9

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser lie Thr Thr Ser 20 25 30

Gly Tyr Tyr Trp Thr Trp He Arg Gin Phe Pro Gly Lys Gly Leu Glu 35 40 45 156874T Sequence Listing.doc 201201840

Trp Met Gly Tyr lie Gly Tyr Asn Ser Lya Thr Tyr Tyr Asn Pro Ala 50 55 60

Leu Lys Ser Arg lie Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu 65 70 75 80

Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Leu Tyr Gly Gly Tyr Lys Asp Ala Phe Asp Ser Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

0 12 3 1 1 X 1 2 2 2 2 VVVV

slslAX <220><223> hCDR2 TSLPR-012-141 <400> 10

Tyr lie Gly Tyr Asn Ser Lys Thr Tyr Tyr Asn Pro Ala Leu Lys Ser 15 10 15 <210> 11 <211> 108 <212> PRT <213>Labor<220><223> Sequence TSLPR- 012_141 (humanized) LC variable region <400>

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Gly Thr Ser 20 25 30

Leu His Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lya Leu Leu lie 35 40 45

Lys Phe Ala Ser Arg Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 -4- 156874 · Sequence Listing.doc 201201840

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Pro Gly Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210> 12 <211> 11 <212> PRT <213> Labor <220><223> 1 CDR1 TSLPR-012_141 <400> 12

Arg Ala Ser Gin Ser lie Gly Thr Ser Leu His 15 10

T L 3 R J 1 7p 人 Λ Λ Λ Λ 0 12 3 1111 2 2 2 2 V V —V IV <220><223> 1CDR2 TSLPR-012_141

I <400> 13

Phe Ala Ser Arg Leu Gin Ser 1 5 <210> 14 <211> 108 <212> PRT <213>Labor<220><223»sequence TSLPR-012_75 (humanized) LC variable region <;'400> 14

Glu He Val Leu Thr Gin Ser Pro Asp Phe Gin Ser Val Thr Pro Lys 1 5 10 15

I

Glu Lys Val Thr lie Thr Cya Arg Ala Ser Gin Ser He Gly Thr Ser 20 25 30 156874 - Sequence Listing.doc 201201840

Leu His Trp Tyr Gin Gin Lys Pro Asp Gin Ser Pro Lys Leu Leu work le 35 40 45

Lys Phe Ala Ser Arg Ser lie Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Asn Ser Leu Glu Ala 65 70 75 80

Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Ser Pro Gly Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210> 15 <211> 7 <212> PRT <213> Labor <220><223> 1 CDR2 TSLPR-012-75 <400> 15

Phe Ala Ser Arg Ser lie Ser 1 5 <210> 16 <211> 122 <212> PRT <213> Labor <220><223> Sequence TSLPR-012_166 (Humanized) HC Variable Area <;400> 16

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin IS 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser lie Thr Thr Ser 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 4S

Trp lie Gly Tyr lie Gly Tyr Asn Ser Lys Thr lyr Tyr Ser Pro Ser 50 55 60 156874 - Sequence Listing.doc 201201840

Leu Lys Ser Arg Val Thr lie Ser Arg Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Leu Tyr Gly Gly Tyr Lys Asp Ala Phe Asp Ser Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 17 <211> 12 <212> PRT <213> Labor <220><223> hCDRl TSLPR-012 166

I <400> 17

I

Gly Phe Ser lie Thr Thr Ser Gly Tyr Tyr Trp Ser 15 10 0 12 3 1111 2 2 2 2 VVVV — 8 TL 8 o1 IP person <220><223> sequence TSLPR-012J66 (humanized) LC variable region <400> 18 lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Gly Thr Ser 20 25 30

Leu His Trp Tyx Gin His Arg Pro Gly Glu Thr Pro Lys Leu Leu lie 35 40 45

Lys Phe Ala Ser Arg Ser lie Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 156874 - Sequence Listing.doc 201201840 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Pro Gly Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 100 105

0 12 3 11X1 2 2 2 2 VVV V 19108 ΓΙ <220><223> Sequence TSLPR-012_189 (Humanized) LC variable region <400>

Glu lie Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser lie Gly Thr Ser 20 25 30

Leu His Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45

Lys Phe Ala Ser Arg Ser lie Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Ser 65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Ser Pro Gly Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys Arg 100 105 <210> 20 <211> 330 <212> PRT <213> Homo sapiens <400> 20

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15 156874 - Sequence Listing.doc 201201840

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125

Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys 130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175

Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190

His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205

Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 210 215 220

Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240

Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 9- 156874, Sequence Listing.doc 201201840

Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn 290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320

Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 127rtda 2 3 p 智 Λ Λ Λ Λ 0 12 3 1111 2 2 2 2 <<<<<400> 21

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95

Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 100 105 110

Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 -10· 156874-Sequence List.doc 201201840

Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140

Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp 145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 165 170 175

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205

Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 210 215 220

Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240

Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 260 265 270

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser ' 275 280 285

Arg Leu Thr Val Asp Lys Ser Arg Gin Glu Gly Asn Val Phe Ser ! 290 295 300

Cys Ser Val Met His Glu Ala Leu His Ass His Tyr Thr Gin Lys Ser 305 310 315 320

Leu Ser Leu Ser Leu Gly Lys 325 <210> 22 <211> 327 <212> PRT <213> Artificial-II - 15687.4 "Sequence Listing.doc 201201840 <220><22 3 > Sequence Human Ig 74 (S228P, L235E) <400> 22

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 IS

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr.Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95

Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110

Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lya Pro Lys 115 120 125

Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thx Cys Val Val Val 130 135 140

Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp 145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 165 170 17S

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205

Pro Ser Ser He Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 210 215 220 b anvil 74 · Sequence Listing.doc 201201840

Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240

Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255

Xle Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys 260 265 270

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285

Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser 290 295 300

Cys Ser Val Met His Glu Ala Leu His Ass His Tyr Thr Gin Lys Ser 305 310 315 320

Leu Ser Leu Ser Leu Gly Lys 325

6 T人2310叩智 Λ Λ Λ Λ 0 12 3 1111 — 2 2 2 2 V VVV <4,00> 23

Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 15 10 15

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30

Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 35 40 45

Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 50 55 60

Tvr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys Sii \ 70 75 80

His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 85 90 95 13- 156874" Sequence Listing.doc 201201840

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 156874 - Sequence Listing, doc •14·

Claims (1)

201201840 VII. Patent Application Range: 1. An antibody that specifically binds to human thymic stromal lymphopoietin receptor (TSLPR) is characterized by comprising a CDR1 region of SEQ ID NO: 2 as a heavy chain variable domain CDR region: , the CDR2 region of SEQ ID NO: 3, and the CDR3 region of SEQ ID NO: 4, and the CDR1 region of SEQ ID NO: 6 as the light chain variable domain CDR I region, and the CDR2 region of SEQ ID NO: And the CDR3 region of SEQ ID NO: 8; or a humanized variant thereof. 2. The antibody of claim 1 wherein the heavy chain variable domain comprises SEQ ID ΝΟ: 1 and the light chain variable domain comprises seQ ID NO: 5. 3. An antibody such as β-green 1 characterized by comprising a CDR1 region of SEQ ID ΝΟ: 2 or 17 as a CDR region of a heavy bond variable domain, a CDR2 region of SEQ ID Ν〇: 3 or 10 and CDR3 region of SEQ ID NO: 4, and CDR1 region of SEQ ID ΝΟ: 6 or 12 as a light chain variable domain CDR region, CDR2 region of SEQ ID 7: 7, 13, or 15, and SEQ ID ΝΟ·· 8 CDR3 area. An antibody according to claim 1, which comprises _a) a CDR1 region of SEQ ID NO: 2, a CDR2 region of SEQ ID NO: 10, and SEQ ID NO: 4 as a heavy chain variable domain CDR region • a CDR3 region, and a CDR1 region of SEQ ID NO: 12, a CDR2 region of SEQ ID NO: 13 and a CDR3 region of SEQ ID NO: 8 as a light chain variable domain CDR region, b) as a heavy chain variable The CDR1 region of SEQ ID NO: 2, the CDR2 region of SEQ ID NO: 10, and the CDR3 region of SEQ ID NO: 4, and the SEQ 156874-doc 201201840 ID of the light chain variable domain cdr region The CDR1 region of NO:12, the CDR2 region of SEQ ID ··15 and the CDR3 region of SEQ ID NO:8, c) the CDR1 region of SEQ ID NO: 17 as the CDR region of the heavy bond variable domain, SEQ ID NO CDR2 region of 10, and CDR3 region of SEQ ID NO: 4 and CDR1 region of SEQ ID NO: 12 as a light chain variable domain CDR region, CDR2 of SEQ ID NO: 15 g & SEQ ID NO: 8tCDR3g, 4 d) the CDR1 region of SEQ ID NO: 2, the CDR2 region of SEQ ID NO: 10, and the CDR3 region of SEQ ID NO: 4, and the CDR region as a light chain variable domain, as a heavy bond variable domain CDR region SEQ ID NO: 12 The CDR1 region, the CDR3 region of SEQ ID NOJ^^CDRZg^^SEQ ID NO:8. 5. The antibody of claim 1, characterized in that a) the heavy chain variable domain comprises SEQ ID NO: 9 and the light chain variable domain comprises SEQ ID ΝΟ: 11, b) the heavy chain variable structure The domain comprises SEQ ID NO: 9 and the light chain variable domain comprises SEQ ID NO: 14, c) the heavy chain variable domain comprises SEQ ID NO: 16 and the light chain variable domain comprises SEQ ID NO: 18, or d) the heavy chain variable domain comprises SEQ ID NO: 9 and the light chain variable domain comprises SEQ ID NO: 19. The antibody according to any one of claims 1 to 5, which is characterized in that it belongs to human IgG1 or IgG4 isotype. The antibody according to any one of claims 1 to 5, which is characterized in that it belongs to human 156874.doc -2 - 201201840 IgG4 isotype, and serine 228 is substituted with an amino acid and lysine 235 is substituted with glutamic acid. Wherein the amino acid residue positions are numbered according to Kabat. The antibody according to any one of claims 1 to 5, which is characterized in that it belongs to the human IgG1 isotype, and is substituted with aminic acid 234 for alanine and lysine 235 for alanine, wherein the amino acid residues are The base position is numbered according to Kabat. A nucleic acid, which is characterized in that it encodes an antibody which specifically binds to human thymic stromal lymphopoietin receptor (Tslpr) according to any one of claims 1 to 8, and is characterized in that it comprises a request item. A nucleic acid of 9 for expression of a specific binding to a Tslpr anti-body in a prokaryotic or eukaryotic host cell. A prokaryotic or eukaryotic host cell comprising the nucleic acid of claim 9. 12. A method of producing a recombinant human or humanized antibody according to any one of claims 1 to 8, characterized in that a nucleic acid such as /month 9 and a cell or cell are expressed in a prokaryotic or eukaryotic host cell The antibody supernatant is used to recover the antibody. 13. A pharmaceutical composition comprising an antibody according to any one of claims 8 to 8. A method of producing a pharmaceutical composition comprising the antibody of any one of claims 1 to 8. 15. 2 A method of producing an agent for treating a disease, which comprises an inclusion body. The use of an antibody according to any one of claims 1 to 8 for the manufacture of a 156874.doc 201201840 pharmaceutical composition. 17. Use of an antibody according to any one of claims 1 to 8 for the manufacture of a medicament. 18. The use of claim 16 or 17, wherein the pharmaceutical composition or medicament is for the treatment of an immune disorder. 19. The antibody of any one of claims 1 to 5 for use in the treatment of a disease. 20. The antibody of claim 19, wherein the disease is an immune disease. 156874.doc